20.500.12556/RUL-155602 Uporaba bioloških in računalniških orodij za načrtovanje, testiranje in sintezo novih zaviralcev β-N-acetilglukozaminil transferaze The use of biological and computational tools to screen, assess and synthesize new potent inhibitors of β-N-acetylglucosaminyl transferase O-GlcNAcilacija je posttranslacijska modifikacija, ki se v celici pojavlja na serinskih in treoninskih ostankih beljakovin. Te aminokisline se modificirajo na svoji hidroksilni funkciji s priključitvijo ß-N-acetilglukozaminskega dela. To uravnavata dva encima O-GlcNAc transferaza (OGT), ki dodaja GlcNAc moeity na protein, in O-GlcNAcase (OGA). O-GlcNAcylation je vključen v številne biološke procese zaradi velike količine spremenjenih beljakovin in njegova disregulacija je bila označena kot pomemben korak pri degenerativnih boleznih, kot so rak, diabetes... Ker je OGT ključni del procesa O-GlcNAcylation, je potencialna terapevtska tarča, njegova inhibicija pa bo morda omogočila nove načine zdravljenja degenerativnih bolezni. V tej študiji raziskujemo nov način odkrivanja in ocenjevanja novih zaviralcev OGT. Po uvedbi testa za testiranje ligandov smo se ukvarjali z različnimi vidiki za izboljšanje obstoječih ali odkrivanje novih inhibitorjev OGT. Z uporabo računalniških orodij, kot je preskok med ogrodji, smo ugotovili, da je za posnemanje interakcije uridina z OGT potreben šestčleni obroč. V zadnjem poglavju poročamo o odkritju dveh novih družin inhibitorjev OGT z uporabo novega orodja za presejanje: Knjižnica kodiranja DNK. Sinteza majhnih knjižnic teh družin skupaj z našim biološkim testom in molekularnim modeliranjem je pokazala, da se ti dve novi družini vežeta na OGT po drugačnem mehanizmu kot dosedanji inhibitorji. O-GlcNAcylation is a post-translational modification occurring inside the cell on Serine and threonine residues of proteins. These amino acids are modified on their hydroxyl function through the attachment of a β-N-acetylglucosamine moiety. It is regulated by two enzymes O-GlcNAc Transferase (OGT) that adds the GlcNAc Moeity on the protein and O-GlcNAcase (OGA). O-GlcNAcylation is involved in multiple biological processes due to the large amount of protein modified and its dysregulation has been flagged as an important step in degeneratve diseases such as cancer, diabetes… As a key part of the O-GlcNAcylation process, OGT is a potential therapeutic target and its inhibition will possibly enable new treatments for degenerative diseases. In this study, we are investigating now way to discover and assess new OGT inhibitors. After implementing an assay to test ligands, we worked on different angles to improve existing or discover new OGT inhibitors. The use of computational tools like scaffold hopping allowed us to point that 6 member ring was needed to mimic uridine interaction with OGT. In our last chapter we report the discovery of two new families of OGT inhibitors using a new screening tool: DNA encode library. The synthesis of small libraries of these family coupled with our bioassay and molecular modeling showed that these two new families are binding to OGT through a different mechanism than the reported inhibitors. OGT O-GlcNAcylation medicinska kemija računalniška kemija biološki preskusi biokemija organska kemija OGT O-GlcNAcylation medicinal chemistry computational chemistry bioassays biochemistry organic chemistry true false false Angleški jezik Slovenski jezik Doktorsko delo/naloga 2024-04-08 11:08:40 2024-04-08 11:08:46 2024-04-09 03:46:01 0000-00-00 00:00:00 2024 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 26294 5449.pdf 5449.pdf 1 461FD72DFD278E9D53E92205686264BF b39f0859b8b8bb2ec60e696d8463dff819a5fca15ac57ffc832dc4464d505f38 9d628768-f587-11ee-937a-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=182573 Fakulteta za farmacijo 0 0 0